In 2007, James Watson eyed his genome for the very first time. Through more than 50 years of scientific and technological advancement, Watson saw the chemical structure he once helped unravel now fused into a personal genetic landscape laid out before him.

Yet there was a small stretch of nucleic acids on chromosome 19 that he preferred to leave uncovered, a region that coded the apolipoprotein E gene. APOE, as it’s called, has been a telling genetic landmark of Alzheimer’s risk, strongly correlated to the disease since the early 90s. Watson’s grandmother suffered from Alzheimer’s, and without any reasonable treatments or suitable preventive strategies, the father of DNA decided the information was too volatile, its revelation creating more potential harm than good.

Watson’s apprehension was warranted. Treatments for Alzheimer’s Disease have consistently failed, sometimes miserably. But as we learn more and more about the brain, it has become apparent that genetics alone rarely dictate the course of disease. Instead, brain disorders result from a complex interaction of our genes and the environments to which we’re exposed. And now, a recent wave of research has unveiled another player in the genesis of neurodegenerative disease: stress.

While scientists have already catalogued the effect of our surroundings and environment on psychological conditions – including depression and anxiety disorders – new studies suggest that stress may also figure into the complex equation that determines if someone will develop a neurodegenerative disease or not. Because stress can be mitigated through lifestyle changes, people may finally gain some control over these devastating, and feared, illnesses.

Since Alois Alzheimer first noted his clinical findings of “presenile dementia” in a patient at the turn of the twentieth century, doctors have continually observed that the disease tends to run through families. But it wasn’t until the early 90s, when a team led by Margaret Pericak-Vance, then a researcher at Duke University Medical School, uncovered the genetic link to Alzheimer’s Disease. By extracting DNA from circulating lymphoblasts, Pericak-Vance and colleagues were able to correlate Alzheimer’s Disease to variations of the APOE gene on chromosome 19.

Around the same time, another group of researchers at Duke University’s Department of Psychiatry and Behavioral Science, led by Brenda Plassman, started a series of experiments to see if non-genetic factors contributed to Alzheimer’s. They wondered: could a person’s environment also affect whether or not they’d acquire the disease?

When studying identical twins, researchers can sift through such questions, says Plassman. If a disease is purely driven by genetics, then when one twin develops the disease, the other twin will be stricken as well. Plassman’s team combed through data collected by the National Academy of Science and National Research Council, which brought together a large cohort of male World Word II veterans, all of whom were identical twins. In February of 2000, Plassman and her colleagues reported that while genetics accounts for much of the occurrence of Alzheimer’s Disease, it can’t explain everything. Other factors were at play, and Plassman’s group has since been looking into whether the disease could be contingent on subtle medical conditions, occupational characteristics, or physical activity levels.

Following suit, a research group led by Mark Tuszynski at the University of California, San Diego, has turned to studying non-human primates, in an effort to explore how different environments might affect the development of the disease. In the January 2011 issue of the Neurobiology of Aging, the team reported a striking association: the size of an animal’s cage, and perhaps the subsequent stress endured by the animals in smaller enclosures, may influence how animals’ brains diminish as they get older. By cataloging the effects of early life experiences on future brain health, researchers may begin to stratify the non-genetic components of cognitive decline and Alzheimer’s Disease progression, discerning whether stress casts its own foreboding shadow on the brain.

In Tuszynski’s study, one group of monkeys, the control group, was raised in standard-sized cages. Another set was raised in cages that were too small for the monkeys to get adequate exercise, and as confirmed by other primate studies, tend to stress the animals, elevating the levels of glucocorticoid hormones circulating through their bodies.

Stress-related glucocorticoids – cortisol in primates and corticosterone in rodents – have been shown to reduce the number of synapses, altering the way brain cells communicate with each other. Several areas of the brain have receptors for glucocorticoids, which may explain how these hormones make their mark on neurons.

Using special proteins that adhere to specific structures in the brain, Tuszynski’s team measured the relative number of synapses, as well as the amount of sticky amyloid plaques that formed in each monkey, both of which are persistent hallmarks of cognition, and frequently used to classify Alzheimer’s Disease. Monkeys raised in smaller cages had, on average, a higher density of plaques and lower number of synapses, the same brain pathology seen postmortem in Alzheimer’s patients.

More or less, all of the primates raised in normal size cages had the same amount of plaque. The monkeys housed in smaller cages as youngsters, on the other hand, had much more variation in their plaque level, suggesting stress may affect individuals in different ways. For some, it’s detrimental, while others appeared to take it in stride.

Clearly, these results only provide a correlative link between early life experience and measures of cognitive function, a retrospective peek that implies stress may be more than an emotional burden. But, as Plassman pointed out, we don’t know whether the brain changes the authors observed translated into true cognitive slips. Tuszynski’s team reported that they were simply not able to run tests on cognitive function for this particular experiment, because some of the older monkeys were brought to them just a few weeks before they died.

While a causal link between stress and Alzheimer’s Disease remains elusive, a bevy of research has shown that moderate stress can in fact make the symptoms of neurodegenerative diseases worse – not just in Alzheimer’s, but in animal models of Parkinson’s Disease, too.

In March 2010, a research team run by Karim Alkadhi at the University of Houston used an “at-risk” model of Alzheimer’s, where doses of amyloid peptides – the same molecules that form the plaques seen in patients – were injected into rats, but at levels much too low to cause any symptoms. The researchers then stressed some of the animals by placing an intruder rat into their home cage, a model which had previously demonstrated a substantial increase of corticosterone in the rats’ bloodstream. By splitting the rodents into four groups, the team was able to tease out whether the sub-clinical dose amyloid peptides and stress treatments worked independently, or in concert, to make the animal’s cognitive abilities worse.

The researchers determined how well each group of rats could learn and remember a new task, by hiding a platform from view in a rodent water maze. Usually, after a few tries, a rat will remember where the platform is located, and have no trouble swimming to it on subsequent days. Only one group had difficulty learning the new task (and remembering where it was located): the animals that received both the amyloid dose and were regularly stressed out. Alkadhi’s results show that chronic stress alone doesn’t alter long-term memory. Similarly, putting an animal at-risk for Alzheimer’s by dosing them with amyloid peptides, does not affect how well they learn. But chronic stress seems to push the at-risk animals over the edge, making them less likely to learn, and remember, new things.

Whereas Alzheimer’s Disease is marked by neurodegeneration in the areas of the brain responsible for memory and general cognitive function, patients suffering from Parkinson’s Disease primarily have motor difficulties, since they lose specialized brain cells that produce dopamine, a chemical essential for voluntary movement. But despite the differences in pathology and symptoms, studies conducted by Gerlinde Metz’s lab at the University of Lethbridge have shown that underlying stress may hasten the disease just the same.

To create a rat model of Parkinson’s Disease, Metz’s team induced a chemical lesion in rats’ brains by infusing a toxic, cell-killing drug into an area rich with dopamine neurons. Additionally, some of the animals were subjected to chronic stress by placing them in a Plexiglas tube for 20 minutes every day during the weeks of the experiment, a procedure known to temporarily elevate the rats’ level of stress hormones. A third group of rats received direct injections of corticosterone, which consistently kept the animals’ stress hormones elevated during the experiment. Getz’s team then used a battery of behavioral tests, including a skilled reaching exercise, where the rats had to slip their paws through a narrow opening in a test chamber, to assess the animals’ motor functions.

Metz’s model of Parkinson’s Disease is transient, and typically, the motor abilities of rats that receive the chemical lesion will spontaneously improve over time. But the researchers showed that even a moderate amount of stress can be harmful: animals with increased corticosterone levels – whether momentarily boosted by stressful environments, or chronically elevated by hormone injection – had continued difficulty with the skilled reaching task, long after the other animals had recovered.

Utilizing eye-opening studies like these, doctors and physicians are learning that stress is more than an emotional problem, deeper than a fleeting mental encumbrance. Our brains constantly rewire themselves throughout our lives, and are strongly driven by experiences, both positive and negative. And it seems that in certain situations, stress is an antagonist that can indeed leave an indelible mark on our brains.

But in stark contrast to the doom-and-gloom we’re accustomed to hearing about Alzheimer’s and Parkinson’s – disheartening research results, or news clips of drug trials where the latest molecular kryptonite has yet again failed – these reports highlight an environmental component of neurodegenerative disease that can, for once, be controlled. Just as many with high cholesterol levels now take preemptive action to stave off heart disease, one day people may use their APOE status, for instance, to make other necessary positive changes in their lives.

Are you a scientist? Have you recently read a peer-reviewed paper that you want to write about? Then contact Mind Matters co-editor Gareth Cook, a Pulitzer prize-winning journalist at the Boston Globe, where he edits the Sunday Ideas section. He can be reached at garethideas AT gmail.com

ABOUT THE AUTHOR(S)

Brian Mossop is the Community Manager at the Public Library of Science (PLoS). He completed his PhD in biomedical engineering at Duke University and did postdoctoral research in behavioral and developmental neuroscience. His work has appeared in Wired, Scientific American, Slate, and elsewhere.

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